Successful propagation of any species depends on the successful completion of pregnancy and delivery of an intact, healthy fetus. Fetal growth and well-being depend on adequate nutrient and oxygen delivery across the placenta, which in turn are dependent on the maintenance and increases in maternal uteroplacental (UPBF) and fetal umbilicoplacental (UmBF) blood flows that normally occur in pregnancy. In the absence of the rise in blood flow or in the presence of maternal nutrient deficiency, fetal growth may be compromised and associated with increased fetal-neonatal mortality and morbidity, preterm birth and pregnancy complications resulting in impaired fetal-neonatal well-being. The long term objective of this project is to determine the mechanisms contributing to the maintenance and rise in UPBF and UmBF, how they relate to cardiovascular adaptation in pregnancy and development and how they are modified by maternal disease states, e.g., diabetes. To address these questions, we will study chronically instrumented nonpregnant, pregnant and fetal sheep, which provide physiologic data and observations that can be explained by parallel studies of biochemical, cellular and molecular changes that relate to regulatory mechanisms, e.g., changes in large conductance Ca2+-activated K+ channels (BKCa) expression and function in uterine vascular smooth muscle (VSM) and regulation of UPBF and estradiol-172 (E2)-mediated VSM hyperpolarization and relaxation through cGMP-dependent mechanisms. In the proposed funding period, we will extend our knowledge of the role of BKCa in the regulation of uterine blood flow (UBF) before, during and after pregnancy, explore its role in the fetal umbilicoplacental circulation, and determine if BKCa dysfunction contributes to abnormal blood flows in specific problems associated with pregnancy, e.g., diabetes and maternal nutrient deficiency, which are world wide problems with an extensive impact on fetal-neonatal morbidity, fetal reprogramming and the occurrence of adult-onset diseases. We will address 5 specific aims: 1) does increased BKCa expression in UA VSM in normal ovine pregnancy begin in the follicular phase of the ovarian cycle, contributing to the rise in UBF and the increased likelihood of successful implantation and placentation; 2) what is the pattern of BKCa expression in the fetal umbilicoplacental circulation during pregnancy and does it contribute to the regulation of UmBF; 3) how does maternal hyperglycemia alter BKCa channel expression and function in the maternal and fetal placental vascular beds, and what is the role of reactive oxygen species and/or cytokines; 4) does maternal nutrient deficiency alter VSM BKCa expression and function contributing to the development of FGR; and 5) what is the role of BKCa in the human uterine vascular bed? These are logical extensions primarily derived from recent and ongoing studies in our labs, but also include important observations by others. These studies will improve our understanding of the regulation of UPBF and UmBF and their contribution to pregnancy complications. PUBLIC HEALTH RELEVANCE: Alterations in the development and increase in maternal uteroplacental and/or fetal umbilicoplacental blood flow during pregnancy contribute to the occurrence of fetal growth restriction, fetal hypoxia/asphyxia and increases in poor pregnancy outcome. The purpose of these studies is to examine the role of K+ channels in the regulation of these blood flows in normal pregnancy, and determine if this is altered in the presence of maternal hyperglycemia, i.e., diabetes, and maternal nutrient deficiency, which are associated with an increase incidence of poor fetal growth and outcome. Understanding these principles may subsequently permit the development of strategies to improve blood flow.